rs781301028

chr19-10137091-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2 BP4_Moderate BP6 BS2

The NM_001130823.3(DNMT1):c.4483G>A(p.Val1495Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000918 in 1,611,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000095 (0 hom.)
• Consequence: DNMT1 NM_001130823.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.923

Genes affected

DNMT1 (HGNC:2976): (DNA methyltransferase 1) This gene encodes an enzyme that transfers methyl groups to cytosine nucleotides of genomic DNA. This protein is the major enzyme responsible for maintaining methylation patterns following DNA replication and shows a preference for hemi-methylated DNA. Methylation of DNA is an important component of mammalian epigenetic gene regulation. Aberrant methylation patterns are found in human tumors and associated with developmental abnormalities. Variation in this gene has been associated with cerebellar ataxia, deafness, and narcolepsy, and neuropathy, hereditary sensory, type IE. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• PP2: Missense variant where missense usually causes diseases, DNMT1
• BP4: Computational evidence support a benign effect (MetaRNN=0.19364479).
• BP6: Variant 19-10137091-C-T is Benign according to our data. Variant chr19-10137091-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 472277.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS2: High AC in GnomAd at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNMT1	NM_001130823.3	c.4483G>A	p.Val1495Met	missense_variant	37/41	ENST00000359526.9
DNMT1	NM_001318730.2	c.4435G>A	p.Val1479Met	missense_variant	36/40
DNMT1	NM_001379.4	c.4435G>A	p.Val1479Met	missense_variant	36/40
DNMT1	NM_001318731.2	c.4120G>A	p.Val1374Met	missense_variant	37/41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNMT1	ENST00000359526.9	c.4483G>A	p.Val1495Met	missense_variant	37/41	1	NM_001130823.3

Frequencies

GnomAD3 genomes AF: 0.0000591 AC: 9 AN: 152224 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000449 AC: 11 AN: 244814 Hom.: 0 AF XY: 0.0000677 AC XY: 9 AN XY: 132900

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000550

Gnomad SAS exome AF: 0.0000332

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000816

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000952 AC: 139 AN: 1459660 Hom.: 0 Cov.: 32 AF XY: 0.000103 AC XY: 75 AN XY: 725960

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000119

Gnomad4 OTH exome AF: 0.0000829

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152224 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74376

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000192

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.0000330 AC: 4

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary sensory neuropathy-deafness-dementia syndrome;C3807295:Autosomal dominant cerebellar ataxia, deafness and narcolepsy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 05, 2021

- -

Hereditary sensory neuropathy-deafness-dementia syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 18, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.63
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.73	D;.
Eigen	Benign	-0.053
Eigen_PC	Benign	-0.10
FATHMM_MKL	Benign	0.39	N
LIST_S2	Uncertain	0.88	D;D
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.19	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.83	L;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.66	N;N
REVEL	Benign	0.14
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.0040	D;D
Polyphen		0.99	D;D
Vest4		0.20
MutPred		0.41		Gain of disorder (P = 0.055);.;
MVP		0.48
MPC		1.7
ClinPred		0.25	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.2
Varity_R		0.19
gMVP		0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs781301028; hg19: chr19-10247767; COSMIC: COSV61576733; COSMIC: COSV61576733;